Synthesis of Sex Steroids

Sex hormones are primarily synthesized in the gonads; but recent studies have provided evidence that these hormones can be synthesized in nongo-nadal tissues (Samy et al., 2000, 2001, 2003; Chaudry et al., 2003). Cholesterol, which is the starting material for sex steroid biosynthesis, is converted to testosterone (Fig. 6.2) in the presence of various enzymes. Testosterone is common to both male and female sex hormones, but its conversion into 5a-DHT or 170-estradiol is highly dependent on the availability of two critical enzymes, 5a-reductase and aromatase, respectively (Brodie and Njar, 2000; Chaudry et al., 2003; Flores et al., 2003; Arora and Potter, 2004; Occhiato et al., 2004). 5a-Reductase enables the conversion of testosterone into male 5a-DHT, whereas aromatase metabolizes the same testosterone

Cholesterol

P450 I

17OH-Pregnenolone

> 17OH-Progesterone

P450 I

17OH-Pregnenolone

P450s

Dehydroepiandrosterone 3ßHSD^ Androstenedione

Androstenediol-► Testosterone

5 a-Reductase Aromatase

5a-Dihydrotestosterone 17ß-Estradiol

17ßHSD

Androsterone (inactive).

Estrone (inactive).

Figure 6.2. Enzymatic pathway for the sex steroid synthesis in healthy conditions. Abbreviations: 3a-HSD, 3a-hydroxysteroid dehydrogenase; 17P-HSD, 17P-hydroxysteroid dehydrogenase.

into female sex steroid 17P-estradiol. Previous studies have shown that the enzymes [5a-reductase, aromatase, 3a-hydroxysteroid dehydrogenase (3a-HSD), 3P-hydroxysteroid dehydrogenase (3P-HSD), and 17P-hydroxysteroid dehydrogenase (17P-HSD)] responsible for the conversion of cholesterol to male or female sex hormones are present in peripheral tissues including spleen and T cells (Samy et al., 2000,2001,2003; Chaudry et al., 2003) (Fig. 6.2). In recent studies, we evaluated whether trauma-hemorrhage affects the expression of these enzymes in immune cells. Findings from these studies have shown that trauma-hemorrhage differentially regulates the expression and activity of 5a-reductase, aromatase, and 17P-HSD in male and female T cells (Samy et al., 2000, 2001, 2003; Chaudry et al., 2003). In males, there was an increase in T-cell 5a-reductase activity after trauma-hemorrhage; aromatase activity on the other hand is relatively low and is not altered after trauma-hemorrhage in T cells derived from male animals (Fig. 6.3A).Thus, a trauma-hemorrhage-mediated increase in T-cell 5a-reductase activity is likely to contribute to increased synthesis of 5a-DHT by these cells. 5a-DHT can be metabolized by 3a-HSD and 17P-HSD, sequentially, into androsterone, a metabolite that is inactive because of its inability to bind to the androgen receptor. However, studies show no alteration in the activity of 3a-HSD and a decrease in the expression of 17P-HSD in male T cells after trauma-hemorrhage (Samy et al., 2000,2001,2003; Chaudry et al., 2003). This suggests a lack of 5a-DHT catabolism in T cells of trauma-hemorrhaged males and consequently results in elevated levels

Figure 6.3. Regulation of 5a-reductase and aromatase activity in T cell after trauma-hemorrhage in males (A) and proestrus females (B).

of 5a-DHT within the cells. 5a-DHT binding affinity to the androgen receptor is severalfold higher than that of testosterone and is considered to be the most potent androgen (Samy et al., 2000, 2001, 2003; Chaudry et al., 2003). Interestingly, findings from these studies further suggested that in castrated animals, trauma-hemorrhage decreases 5a-reductase activity and increases expression of 170-HSD, suggesting inactivation of 5a-DHT in castrated males. Altogether, these findings suggest that increased synthesis and decreased catabolism of 5a-DHT is likely the principal cause for the loss of T-cell functions in intact males after trauma-hemorrhage (Samy et al.,

2000, 2001, 2003; Zheng et al., 2002; Chaudry et al., 2003; Schneider et al., 2003).

T cells in the proestrus females, on the other hand, have low 5a-reductase activity and thus low 5a-DHT levels (Fig. 6.3B). In contrast, aro-matase as well as 17P-HSD activities significantly increase in proestrus females after trauma-hemorrhage (Fig. 6.3B), suggesting increased synthesis of 17p-estradiol (Samy et al., 2000, 2001, 2003; Zheng et al., 2002; Chaudry et al., 2003). The lack of change in 17P-HSD oxidative activities leads to less conversion of 17P-estradiol to estrone, which is an inactive metabolite and does not bind to estrogen receptors. In contrast, activities of aromatase and 17P-HSD are low in the T cells of the ovariectomized animals as compared with the proestrus females after trauma-hemorrhage (Samy et al., 2000,2001,2003; Zheng et al., 2002; Chaudry et al., 2003). This results in lower 17P-estradiol production and consequent immunosuppression. Whether similar alteration in steroidogenesis occurs in other organs such as heart and liver remains to be established. Findings obtained from immune cells suggest that steroidogenic enzymes differ between males and proestrus females and that the trauma-hemorrhage further influences the activity of these enzymes. Because the synthesis of active steroids markedly influences cytokine production, these enzymes may serve as potential targets for therapeutic modulation after trauma-hemorrhage.

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